Extensive, robust evidence indicates that mitochondrial abnormalities and oxidative stress occur in Alzheimer's disease (AD) as well as in Huntington's disease (HD) and other neurodegenerative disorders. Recent studies from several laboratories link mitochondrial damage to AD amyloid. The proposed experiments will elucidate the fundamental mechanisms of mitochondrial damage in AD and how they contribute to brain damage. Huntington's disease (HD) will also be studied because of the mechanistic insights it offers. The overall hypothesis is: mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. This proposal tests the possibility that genetic variation (including genes that cause AD or HD) and/or environmental insults may produce mitochondrial dysfunction by altering the activities or production of proteins whose actions modify mitochondria proteins and function. The mechanism by which the resulting abnormalities promote neurodegeneration will be tested at multiple levels of biological complexity: gene transcription, proteins, mitochondria, intact cultured cells, transgenic mice and human brains. The experiments will focus on two enzyme systems that are markedly altered in diseased brains: the proteins that form the key mitochondrial enzyme a-ketoglutarate dehydrogenase complex (KGDHC) and transglutaminase (TGase). Brain KGDHC activity declines in AD and HD. The reduction correlates highly with clinical state, at least in AD. The Program Project will test why KGDHC is decreased and the implications of the reduction for mitochondrial function, for cellular interactions and for neurodegeneration. Our studies have shown marked increases in TGase products in AD and HD in both brain and CSF. The proposed experiments will test whether changes in TGase activity alters transcriptional mechanisms, inactivates mitochondrial enzymes including KGDHC, and causes accumulation of TGase products that can aid diagnosis. We will identify improved TGase inhibitors and test whether they and/or agents that promote mitochondrial function will delay pathological and pathophysiological changes in transgenic mouse models of AD and HD. Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations including AD. [unreadable] [unreadable] PRINCIPAL INVESTIGATOR [unreadable] [unreadable] Dr. Gary Gibson is a Professor of Neurology at the Weil Medical School of Cornell University. He is an established investigator and an author of many pioneering studies on the relationship between mitochondrial function and neurodegeneration. His record of research productivity is impressive and he and his group are well suited to carry out the proposed research. [unreadable] [unreadable] [unreadable]